Histamine is normally stored within intracellular granules in mast cells, lung, liver and gastric mucosa, etc. and released from the cell in response to external stimuli such as antigen-binding to an antibody on the cell surface. For example, when mast cells are stimulated by an antigen entering from outside, histamine is released from the mast cells and stimulates histamine H1 (H1) receptors located on blood vessels or smooth muscles, thereby triggering an allergic reaction. Likewise, histamine released from ELC cells (enterochromaffin-like cells) on the gastric mucosa stimulates histamine H2 (H2) receptors on the parietal cells to promote gastric acid secretion. Based on these facts, H1 and H2 receptor antagonists have been developed as therapeutic agents for allergic diseases and gastric ulcer, respectively, and currently find wide use as medicaments.
It has been found that histamine serves as a neurotransmitter and acts on histamine receptors (histamine H3 (H3) receptors) located on the central and peripheral nerves to exhibit various physiological functions. This receptor was cloned in 1999, and its gene sequence and amino acid sequence were determined. However, the amino acid sequence of H3 receptor has only 22% and 21.4% homology with those of H1 receptor and H2 receptor, respectively (see Non-Patent Document 1). H3 receptors which are present in the presynaptic membrane have been shown to serve as autoreceptors that control the synthesis and release of histamine (see Non-Patent Document 2). In addition to that, H3 receptors have been shown to control the release of other neurotransmitters including acetylcholine, serotonin, dopamine, and noradrenaline (see Non-Patent Document 3). It has also been suggested that H3 receptors are active in the absence of agonists and this activity is able to be inhibited by compounds acting as inverse agonists. These facts suggest that H3 receptor antagonists or inverse agonists enhance the release of H3 receptor-controlled neurotransmitters and may potentially serve as therapeutic agents for various diseases associated with abnormal release thereof.
As a matter of fact, results of experiments with animal models show the possibility that H3 receptor antagonists or inverse agonists can be used as therapeutic agents for dementia, Alzheimer's disease (see Non-Patent Documents 4 and 5), attention-deficient hyperactivity disorder (see Non-Patent Document 6), schizophrenia (see Non-Patent Document 7), epilepsy, central convulsion, etc.
It has been shown that H3 receptors are involved in the eating behavior (see Non-Patent Document 8) and metabolic diseases including obesity, diabetes mellitus, hyperlipidemia, etc. are also assumed as diseases for which H3 receptor antagonists or inverse agonists are indicated.
It has been shown that histamine regulates the circadian rhythm in the brain and is responsible for maintaining the balance between waking and sleeping states (see Non-Patent Documents 9 and 10) and diseases associated with sleep disorders, including narcolepsy, idiopathic hypersomnia, behaviorally induced insufficient sleep syndrome, sleep apnea syndrome, circadian rhythm disorder, parasomnia, sleep related movement disorder, insomnia, and depression, are also assumed as diseases for which H3 receptor antagonists or inverse agonists are indicated.
It has been shown that H3 receptors are present in sympathetic nerves on the nasal mucosa, and reported that the combined use of H3 and H1 receptor antagonists improved nasal congestion significantly (see Non-Patent Document 11). This indicates the possibility that H3 receptor antagonists or inverse agonists are useful for treatment of such diseases as allergic rhinitis when they are used either alone or in combination with H1 receptor antagonists.
Outlines of H3 receptor antagonists or inverse agonists are found in several reviews (see Non-Patent Documents 12 to 15) to which reference may be had. In earlier years, there have been reported many imidazole compounds which were derived from histamine itself as a lead compound. However, those have yet to be developed as medicaments due to the concerns of the inhibition of the drug-metabolizing enzyme cytochrome P450 (CYP).
In recent years, non-imidazole H3 receptor antagonists or inverse agonists have been reported in many documents and patents (see Patent Documents 1 to 10).
Reports have also been made of histamine H3 receptor antagonists having 5-membered aromatic rings such as the pyrazole ring (see Patent Documents 11 to 14). In addition, there has been reported a histamine H3 receptor antagonist having an aryloxypiperidine skeleton that is substituted by an unsubstituted pyrrole (see Patent Document 15). However, there has been no report about compounds having the structures disclosed hereinafter.